Sodium hydride → 1-Cyclopentyl-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-methylsulfanyl-4H-pyrimido[4,5-D]pyrimidin-2-one

HRID 459960Notes

Reaction equation

HRID 459960 reaction equation
[CH:1]1([NH:6][C:7]2[C:12]([CH2:13][NH:14][C:15]3[C:20]([F:21])=[C:19]([O:22][CH3:23])[CH:18]=[C:17]([O:24][CH3:25])[C:16]=3[F:26])=[CH:11][N:10]=[C:9]([S:27][CH3:28])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32]>O1CCCC1>[CH:1]1([N:6]2[C:7]3=[N:8][C:9]([S:27][CH3:28])=[N:10][CH:11]=[C:12]3[CH2:13][N:14]([C:15]3[C:16]([F:26])=[C:17]([O:24][CH3:25])[CH:18]=[C:19]([O:22][CH3:23])[C:20]=3[F:21])[C:31]2=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 682631,1'-CarbonyldiimidazoleHCID 18444835Cyclopentyl-(5-[(2,6-difluoro-3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl)-amine

Product 1

HCID 184446921-Cyclopentyl-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-methylsulfanyl-4H-pyrimido[4,5-D]pyrimidin-2-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 16.33 g (0.0398 mol) of cyclopentyl-(5-[(2,6-difluoro-3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl)-amine in 288 mL of anhydrous tetrahydrofuran was cooled to 0° C. using an ice/acetone bath. The reaction mixture was treated with 3.98 g (0.0995 mol) of sodium hydride and continued stirring at 0° C. for 30 minutes. After 30 minutes, 19.35 g (0.019 mol) 1,1′-carbonyldiimidazole was added and continued to stir at 0° C. for an additional 30 minutes. After 1 hour, the ice bath was removed and the reaction mixture was allowed to warm up to room temperature. The reaction mixture heated at reflux overnight under nitrogen atmosphere. Evaporated the tetrahydrofuran and partitioned the residue between dichloromethane and water. The aqueous layer was extracted one time with 500 mL dichloromethane. The dichloromethane extracts were combined, dried over sodium sulfate, filtered and evaporated. There was a portion of the crude material that did not dissolve in the eluent. Filtered the solid and dried in the housevac oven overnight to give the title compound, 6.80 g of crop 1. The remaining crude material was purified using medium pressure-chromatography, eluting with a gradient of 2:1 hexanes/ethyl acetate to 1:1 hexanes/ethyl acetate to give the title compound as a white solid, 8.74 g of crop 2. Combined the crops to give a total of 15.54 g (90%) of the title compound. MS (APCI) (m+1)/z 437.1.

Workup

  1. waitAfter 30 minutes
  2. stirringto stir at 0° C. for an additional 30 minutes
  3. waitAfter 1 hour
  4. customthe ice bath was removed
  5. temperatureto warm up to room temperature
  6. temperatureThe reaction mixture heated
  7. temperatureat reflux overnight under nitrogen atmosphere
  8. customEvaporated the tetrahydrofuran
  9. custompartitioned the residue between dichloromethane and water
  10. extractionThe aqueous layer was extracted one time with 500 mL dichloromethane
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. customevaporated
  14. dissolutiondid not dissolve in the eluent
  15. filtrationFiltered the solid
  16. customdried in the housevac oven overnight

Sources & evidence

ORD record
ord-3db932646aa645ec92e94872c5e205f2
Source dataset
uspto-grants-2007_03
Patent number
US07196090B2

Reaction notes

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